U.S. patent number 6,001,831 [Application Number 09/029,723] was granted by the patent office on 1999-12-14 for process for producing quinazoline derivatives.
This patent grant is currently assigned to Clariant GmbH. Invention is credited to Stefan Krause, Doris Neumann-Grimm, Theodor Papenfuhs, Ralf Pfirmann.
United States Patent |
6,001,831 |
Papenfuhs , et al. |
December 14, 1999 |
Process for producing quinazoline derivatives
Abstract
A process for producing
1,2,3,4-tetrahydro-2,4-dioxo-quinazoline-1-yl acetic acid
derivatives of the formula (I) in which R.sup.1, R.sup.2, R.sup.3
and R.sup.4 are mutually independently hydrogen, halogen, OH,
NO.sub.2, (C.sub.1 -C.sub.6) alkoxy, (C.sub.1 -C.sub.6) alkyl,
halogen-substituted (C.sub.1 -C.sub.6) alkyl, R.sup.5 is hydrogen,
(C.sub.1 -C.sub.6) alkyl, phenyl where the alkyl or phenyl radical
may also be substituted by halogen atoms; in which an anthranilic
acid derivative of formula (II), in which R.sup.1 to R.sup.5 have
the above meaning and R.sup.6 is hydrogen, (C.sub.1 -C.sub.6) alkyl
or phenyl, where the alkyl or phenyl radical may also be
substituted by halogen atoms, is reacted with a metal cyanate and
hydrogen chloride in the presence of an inert solvent. ##STR1##
Inventors: |
Papenfuhs; Theodor (Frankfurt,
DE), Pfirmann; Ralf (Griesheim, DE),
Krause; Stefan (Frankfurt, DE), Neumann-Grimm;
Doris (Frankfurt, DE) |
Assignee: |
Clariant GmbH (Frankfurt,
DE)
|
Family
ID: |
7770850 |
Appl.
No.: |
09/029,723 |
Filed: |
May 22, 1998 |
PCT
Filed: |
August 19, 1996 |
PCT No.: |
PCT/EP96/03632 |
371
Date: |
May 22, 1998 |
102(e)
Date: |
May 22, 1998 |
PCT
Pub. No.: |
WO97/08154 |
PCT
Pub. Date: |
March 06, 1997 |
Foreign Application Priority Data
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Aug 31, 1995 [DE] |
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195 32 052 |
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Current U.S.
Class: |
514/249;
544/349 |
Current CPC
Class: |
C07D
239/96 (20130101) |
Current International
Class: |
C07D
239/96 (20060101); C07D 239/00 (20060101); A01N
043/66 (); C07D 241/36 () |
Field of
Search: |
;514/249 ;544/349 |
Foreign Patent Documents
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0176333 |
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Apr 1986 |
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EP |
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0218999 |
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Apr 1987 |
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EP |
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142507 |
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Jun 1903 |
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DE |
|
19532054 |
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Mar 1997 |
|
DE |
|
Other References
Derwent Abstract--DE 19532054 A1--German Patent issued Mar. 6,
1997. .
J. Am. Chem. Soc. (1933), pp. 2113-2116, "Quinazolines," by Lange
& Sheibley. .
Journal of the Chemical Society:(1948) Synthetic Antimalarials p.
1759-1766. .
Susse et. al., Monatsh Chem. (1987), vol. 118, pp. 71-79..
|
Primary Examiner: Shah; Mukund J.
Assistant Examiner: Truong; Tamthom N.
Attorney, Agent or Firm: Hanf; Scott E.
Claims
We claim:
1. A process for the preparation of a
1,2,3,4-tetrahydro-2,4-dioxo-quinazolin-1-ylacetic acid derivative
of the formula (I) ##STR4## in which R.sup.1, R.sup.2, R.sup.3,
R.sup.4 independently of one another are hydrogen, halogen,
NO.sub.2, (C.sub.1 -C.sub.6)alkoxy, (C.sub.1 -C.sub.6)alkyl or
halogen-substituted (C.sub.1 -C.sub.6)alkyl and
R.sup.5 is hydrogen, (C.sub.1 -C.sub.6)alkyl or phenyl, where the
alkyl or phenyl radical can also be substituted by halogen
atoms,
which comprises reacting an anthranilic acid derivative of the
formula (II) ##STR5## in which R.sup.1 to R.sup.5 have the
abovementioned meaning and R.sup.6 is hydrogen, (C.sub.1
-C.sub.6)alkyl or phenyl, where the alkyl or phenyl radical can
also be substituted by halogen atoms, with a metal cyanate and
hydrogen chloride in the presence of an inert solvent.
2. The process as claimed in claim 1, wherein R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 independently of one another are hydrogen,
fluorine, chlorine, (C.sub.1 -C.sub.4)alkoxy, (C.sub.1
-C.sub.4)alkyl or chlorine- or fluorine-substituted (C.sub.1
-C.sub.4)alkyl and
R.sup.5 and R.sup.6 are hydrogen, (C.sub.1 -C.sub.4)alkyl or
phenyl.
3. The process as claimed in claim 1, wherein
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 independently of one another
are hydrogen, fluorine, chlorine, methyl or ethyl and
R.sup.5 and R.sup.6 are hydrogen, methyl or ethyl.
4. The process as claimed in claim 1, wherein two of the radicals
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are hydrogen.
5. The process as claimed in claim 1, wherein formula (I) is ethyl
1,2,3,4-tetrahydro-7-chloro-2,4-dioxoquinazolin-1-ylacetate, methyl
1,2,3,4-tetrahydro-7-chloro-2,4-dioxoquinazolin-1-ylacetate or
1,2,3,4-tetrahydro-7-chloro-2,4-dioxoquinazolin-1-ylacetic
acid.
6. The process as claimed in claim 1, wherein a polar aprotic
solvent is employed as the inert solvent.
7. The process as claimed in claim 1, wherein an alkali metal
cyanate or alkaline earth metal cyanate is employed as the metal
cyanate.
8. The process as claimed in claim 1, wherein the concentration of
the anthranilic acid in the solvent is 1 to 50% by weight.
9. The process as claimed in claim 1, wherein the metal cyanate is
added in an amount of 0.8 to 20 molar equivalents based on the
anthranilic acid derivative.
10. The process as claimed in claim 1, wherein the hydrogen
chloride is added in gaseous form or as a non-aqueous solution.
11. The process as claimed in claim 1, wherein the anthranilic acid
derivative and the metal cyanate are initially introduced into the
solvent and hydrogen chloride is metered in.
12. The process as claimed in claim 1 wherein the anthranilic acid
derivative and hydrogen chloride are initially introduced and the
metal cyanate is metered in.
13. The process as claimed in claim 1 wherein hydrogen chloride and
the metal cyanate are initially introduced and the anthranilic acid
derivative is metered in.
14. The process as claimed in claim 1, wherein the reaction
temperature is between 0 and 100.degree. C.
15. The process as claimed in claim 1, wherein the reaction time is
between 15 minutes and 24 hours.
16. The process as claimed in claim 6, wherein said polar aprotic
solvent is selected from the group of: sulfolane, dimethyl
sulfoxide, dimethyl sulfone, diphenyl sulfone and
tetramethylurea.
17. The process as claimed in claim 6, wherein said polar aprotic
solvent is sulfolane.
18. The process as claimed in claim 7, wherein said alkali metal
cyanate or alkaline earth metal cyanate is sodium cyanate or
potassium cyanate.
19. The process as claimed in claim 1 wherein three of the radicals
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are hydrogen.
Description
The present invention relates to a novel process for the
preparation of 1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-ylacetic
acid derivatives.
1,2,3,4-Tetrahydro-2,4-dioxoquinazolin-1-ylacetic acid and
derivatives thereof are important intermediate products for the
preparation of aldose reductase inhibitors (EP 218 999).
J. Am. Chem. Soc. (1933), pages 2113-2116 describes the reaction of
N-ethylanthranilic acid with sodium cyanate and acetic acid and
subsequent addition of sodium hydroxide to give
1,2,3,4-tetrahydro-1-ethyl-2,4-dioxoquinazoline. However,
disadvantages of this process are the low space yield, because of
the dilute reaction solution, and the very high excess of sodium
hydroxide.
Monatsh. Chem. (1987) 118; pages 71-79 describes the reaction of
methyl N-(methoxycarbonylmethyl)anthranilate with potassium cyanate
in glacial acetic acid to give methyl
1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-ylacetate. Although 10
equivalents of potassium cyanate are employed, the yield is only
19%.
There was therefore the need for an efficient process for
conversion of anthranilic acid into
1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-ylacetic acid
derivatives.
This object is achieved by a process for the preparation of
1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-ylacetic acid derivatives
of the formula (I) ##STR2## in which R.sup.1, R.sup.2, R.sup.3,
R.sup.4 independently of one another are hydrogen, halogen,
NO.sub.2, (C.sub.1 -C.sub.6)alkoxy, (C.sub.1 -C.sub.6)alkyl or
halogen-substituted (C.sub.1 -C.sub.6)alkyl and
R.sup.5 is hydrogen, (C.sub.1 -C.sub.6)alkyl or phenyl, where the
alkyl or phenyl radical can also be substituted by halogen
atoms,
which comprises reacting an anthranilic acid derivative of the
formula (II) ##STR3## in which R.sup.1 to R.sup.5 have the
abovementioned meaning and R.sup.6 is hydrogen, (C.sub.1
-C.sub.6)alkyl or phenyl, where the alkyl or phenyl radical can
also be substituted by halogen atoms, with a metal cyanate and
hydrogen chloride in the presence of an inert solvent.
The process is important for the reaction of compounds of the
formula (II) in which R.sup.1, R.sup.2, R.sup.3, R.sup.4 are
hydrogen, fluorine, chlorine, (C.sub.1 -C.sub.4)alkoxy, (C.sub.1
-C.sub.4)alkyl, or chlorine- or fluorine-substituted (C.sub.1
-C.sub.4)alkyl and R.sup.5 and R.sup.6 are hydrogen, (C.sub.1
-C.sub.4)alkyl or phenyl.
The reactions of compounds of the formula (II) in which R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 are hydrogen, fluorine, chlorine,
methyl or ethyl,
and R.sup.5 and R.sup.6 are hydrogen, methyl or ethyl are important
here.
The process is also particularly important for the preparation of
compounds of the formula (I) in which two, and preferably three, of
the radicals R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are
hydrogen.
The process is of particular interest for the preparation of
1,2,3,4-tetrahydro-7-chloro-2,4-dioxoquinazolin-1-ylacetic acid and
the methyl and ethyl ester thereof.
In many cases, it has proved appropriate for the reaction to
initially introduce the anthranilic acid derivatives of the formula
(II) in a solvent. The anthranilic acid can be present here in
dissolved form or as a suspension. Solvents which can be used are
aprotic solvents or protic organic solvents or mixtures of these
solvents. The use of polar aprotic solvents which show no reaction
under the reaction conditions, for example sulfolane, dimethyl
sulfoxide, dimethyl sulfone, diphenyl sulfone, tetramethylurea or
mixtures thereof, is advantageous.
The concentration of anthranilic acid in the solvent is between 1
and 50% by weight, advantageously between 1.5 and 20% by weight,
preferably between 3 and 10% by weight.
Metal cyanates which can be employed are alkali metal and alkaline
earth metal cyanates, and also mixtures thereof. The use of sodium
cyanate or potassium cyanate or mixtures thereof is
advantageous.
It has proved favorable to add the metal cyanates in amounts of
between 0.8 and 20 equivalents, in particular between 2 and 5
equivalents, based on the anthranilic acid derivatives. The metal
cyanates can be initially introduced together with the anthranilic
acid or added continuously or in portions. Hydrogen chloride can be
added in gaseous form or as a non-aqueous solution, in one portion,
in several portions or continuously, and continuous introduction of
hydrogen chloride until the reaction has ended is advantageous.
The reaction partners metal cyanate, hydrogen chloride and
anthranilic acid can be added to the reaction in any desired
sequence, and it is advantageous to initially introduce the
anthranilic acid and metal cyanate and to subsequently meter in the
hydrogen chloride, or to initially introduce the hydrogen chloride
and anthranilic acid and to subsequently meter in the metal
cyanate, or to initially introduce the potassium cyanate and
hydrogen chloride and to meter in the anthranilic acid, or to carry
out combinations thereof.
The reaction temperature is between the solidification point of the
solvent and 150.degree. C., advantageously between 0 and
100.degree. C., particularly advantageously between 20 and
75.degree. C.
The reaction times are between 15 minutes and 24 hours,
advantageously between 1 and 15 hours, particularly advantageously
between 2 and 10 hours.
The reaction can be carried out under reduced, increased or normal
pressure, and it is advantageously carried out under normal
pressure.
The fact that the smooth course of the reaction is particularly
surprising is demonstrated by the comparison example. It shows that
the reaction can in no way be catalyzed generally by acids, but
that the choice of the acid HCl is of decisive importance. The
synthesis of the anthranilic acids of the formula (II) is described
in the U.S. patent application Ser. No. 09/029,414, filed Apr. 4,
1998.
The following examples illustrate the invention without limiting
it.
EXAMPLE 1
Preparation of ethyl
1,2,3,4-tetrahydro-7-chloro-2,4-dioxoquinazolin-1-ylacetate from
4-chloro-N-(ethoxycarbonylmethyl)anthranilic acid.
Hydrogen chloride is passed into 1 g of
4-chloro-N-(ethoxycarbonylmethyl)anthranilic acid and 1.6 g of
potassium cyanate in 20 ml of sulfolane at 50.degree. C. until
analysis by HPLC indicates complete conversion. The product is
precipitated by addition of water, filtered off, washed with water
and dried. 0.95 g (87%) of ethyl
1,2,3,4-tetrahydro-7-chloro-2,4-dioxoquinazolin-1-ylacetate is
obtained.
Melting point: 242-243.degree. C., .sup.1 H NMR (DMF): 1.25 (t,
J=7.0 Hz, --CH.sub.3), 4.21 (q, J=7.0 Hz, O--CH.sub.2 --), 5.00 (s,
N--CH.sub.2), 7.38 (dd, J=1.8 Hz, J=8.2 Hz, 6-H), 7.70 (d, J=1.8
Hz, 8-H), 8.09 (d, J=8.2 Hz, 5-H), 11.86 (s, N--H).
EXAMPLE 2
Preparation of methyl
1,2,3,4-tetrahydro-7-chloro-2,4-dioxoquinazolin-1-ylacetate from
methyl 4-chloro-N-(methoxycarbonylmethyl)-anthranilate.
Hydrogen chloride is passed into 1 g of methyl
4-chloro-N-(methoxycarbonylmethyl)anthranilate and 1.6 g of
potassium cyanate in 20 ml of sulfolane at 50.degree. C. until
analysis by HPLC indicates complete conversion. The product is
precipitated by addition of water, filtered off, washed with water
and dried. 0.59 g (57%) of methyl
1,2,3,4-tetrahydro-7-chloro-2,4-dioxoquinazolin-1-ylacetate is
obtained.
Melting point: 255-258.degree. C. .sup.1 H-NMR (DMSO-d.sub.6): 3.71
(s, --CH.sub.3), 4.92 (s, N--CH.sub.2), 7.33 (dd, J=1.5 Hz, J=8.5
Hz, 6-H), 7.60 (d, J=1.5 Hz, 8-H), 8.01 (d, J=8.5 Hz, 5-H).
EXAMPLE 3
Preparation of
1,2,3,4-tetrahydro-7-chloro-2,4-dioxoquinazolin-1-ylacetic acid
from N-carboxymethylene-4-chloroanthranilic acid.
Hydrogen chloride is passed into a mixture of 20 ml of sulfone and
1.6 g of potassium cyanate at 25.degree. C. to saturation. 1 g of
N-carboxymethylene-4-chloroanthranilic acid is then added and the
mixture is heated to 50.degree. C. After three hours, analysis by
HPLC indicates complete conversion into
1,2,3,4-tetrahydro-7-chloro-2,4-dioxoquinazolin-1-ylacetic
acid.
Melting point: 278-282.degree. C. .sup.1 H-NMR: (DMSO-d.sub.6):
4.71 (s, N--CH.sub.2), 7.30 (dd, J=1.5 Hz, J=8.5 Hz, 6H), 7.41 (d,
J=1.5 Hz, 8-H), 7.99 (d, J=8.5 Hz, 5-H), 11.75 (s, N--H).
EXAMPLE 4
Preparation of ethyl
1,2,3,4-tetrahydro-7-chloro-2,4-dioxoquinazolin-1-ylacetate from
4-chloro-N-(ethoxycarbonylmethyl)anthranilic acid.
A total of 128 g of potassium cyanate and 144 g of hydrogen
chloride are metered into 700 g of sulfolane at 15-20.degree. C.
over a period of 5 hours. For this, 14.4 g of hydrogen chloride are
first passed in and 12.8 g of potassium cyanate are then added;
this operation is repeated 10 times, until the entire amount of
hydrogen chloride and potassium cyanate has been added. 117 g of
4-chloro-N-(ethoxycarbonylmethyl)anthranilic acid are then added at
45-50.degree. C. in the course of 2 hours. The mixture is
subsequently stirred for 15 minutes. The suspension is filtered and
the residue is washed free from sulfolane and salt with water.
After drying, 121 g (95%) of ethyl
1,2,3,4-tetrahydro-7-chloro-2,4-dioxoquinazolin-1-ylacetate are
obtained.
EXAMPLE 5
Preparation of iso-propyl
1,2,3,4-tetrahydro-7-chloro-2,4-dioxoquinazolin-1-ylacetate from
7-chloro-N-(isopropoxycarbonylmethyl)anthranilic acid.
Hydrogen chloride is passed into a mixture of 10 g of sulfolane and
1.3 g of potassium cyanate at 20.degree. C. to saturation. 1 g of
7-chloro-N-(isopropoxycarbonylmethyl)anthranilic acid is then added
at 50.degree. C. and the mixture is subsequently stirred for 30
minutes. The reaction mixture is poured onto water and filtered and
the residue is washed with water and dried. 0.85 g (78%) of
iso-propyl
1,2,3,4-tetrahydro-7-chloro-2,4-dioxoquinazolin-1-ylacetate is
obtained.
.sup.1 H-NMR (DMSO-d.sub.6): 1.21 (d, J=6.3 Hz, H.sub.3
C--C--CH.sub.3), 4.88 (s, N--CH.sub.2), 4.97 (sept, J=6.3 Hz,
O--CH), 7.33 (dd, J=1.7 Hz, J=8.4 Hz, 6-H), 7.53 (d, J=1.7 Hz,
8-H), 8.00 (d, J=8.4 Hz, 5-H), 11.83 (s, N--H).
EXAMPLE 6
Preparation of n-hexyl
1,2,3,4tetrahydro-7-chloro-2,4dioxoquinazolin-1-ylacetate from
7-chloro-N-(n-hexoxycarbonylmethyl)anthranilic acid.
Procedure as under Example 5
Yield: 0.95 g (8%) .sup.1 H-NMR (DMSO-d.sub.6): 0.84 (m, n-hexyl),
1.22 (m, n-hexyl), 1.55 (m, n-hexyl), 4.07 (m, n-hexyl), 4.92 (s,
N--CH.sub.2), 7.33 (dd, J=1.5 Hz, J=8.4 Hz, 6-H), 7.55 (d, J=1.5
Hz, 8-H), 8.01 (d, J=8.4 Hz, 5-H), 11.84 (s, N--H).
EXAMPLE 7
Preparation of benzyl
1,2,3,4tetrahydro-7-chloro-2,4-dioxoquinazolin-1-ylacetate from
7-chloro-N-(benzoxycarbonylmethyl)anthranilic acid.
Procedure as under Example 5.
Yield: 0.80 g (74%) .sup.1 H-NMR (DMSO-d.sub.6): 5.01 (s,
--CH.sub.2 --), 5.22 (s, --CH.sub.2 --), 7.36 (m, 6-H, aromatic-H),
7.59 (d, J=1.7 Hz, 8-H), 8.01 (d, J=8.4 Hz, 5-H), 11.86 (s,
N--H).
EXAMPLE 8
Preparation of ethyl
1,2,3,4tetrahydro-5-fluoro-2,4-dioxoquinazolin-1-ylacetate from
6-fluoro-N-(ethoxycarbonylmethyl)anthranilic acid.
Procedure as under Example 5.
Yield: 0.60 g (54%). .sup.1 H-NMR (DMSO-d.sub.6): 1.21 (t, J=7.1
Hz, --CH.sub.3), 4.16 (q, J=7.1 Hz, --O--CH.sub.2), 4.89 (s,
N--CH.sub.2), 7.06 (dd, J=8.5 Hz, J=11.0 Hz, aromatic-H), 7.14 (d,
J=18.6 Hz, aromatic-H), 7.70 (dd, J=5.8 Hz, J=8.5 Hz, aromatic-H),
11.71 (s, N--H).
EXAMPLE 9
Preparation of ethyl
1,2,3,4-tetrahydro-8-chloro-2,4-dioxoquinazolin-1-ylacetate from
3-chloro-N-(ethoxycarbonylmethyl)anthranilic acid.
Procedure as under Example 5.
Yield: 0.70 g (64%). .sup.1 H-NMR (DMSO-d.sub.6): 1.21 (t, J=7.1
Hz, --CH.sub.3), 4.19 (q, J=7.1 Hz, --O--CH.sub.2), 5.04 (s,
N--CH.sub.2), 7.30 (dd, J.sub.1 =J.sub.2 =7.8 Hz, aromatic -H),
7.81 (dd, J=1.7 Hz, J=7.8 Hz, aromatic-H), 8.04 (dd, J=1.7 Hz,
J=7.8 Hz, aromatic-H), 11.97 (s, N--H).
EXAMPLE 10
Preparation of ethyl
1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazolin-1-ylacetate from
5-nitro-N-(ethoxycarbonylmethyl)anthranilic acid.
Procedure as under Example 5.
.sup.1 H-NMR (DMSO-d.sub.6): 1.22 (t, J=1.22 Hz, --CH.sub.3), 4.18
(q, J=7.1 Hz, O--CH.sub.2), 4.98 (s, N--CH.sub.2), 12.19 (s,
N--H).
COMPARISON EXAMPLE 1
1 ml of concentrated sulfuric acid is added dropwise to 1 g of
4-chloro-N-(ethoxycarbonylmethyl)anthranilic acid and 1.6 g of
potassium cyanate in 20 ml of sulfolane at 50.degree. C. After 5
hours, analysis by HPLC indicates no conversion.
COMPARISON EXAMPLE 2
2.4 g of acetic acid are added to 1 g of
4-chloro-N-(ethoxycarbonylmethyl)anthranilic acid and 1.6 g of
potassium cyanate in 20 ml of sulfolane and the mixture is stirred
at 50.degree. C. After a reaction time of 6 hours, analysis by HPLC
indicates a conversion of about 5%.
* * * * *